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WO2023182869A1 - Nouveau sel de composé agoniste du récepteur glp-1, son procédé de préparation et composition pharmaceutique le comprenant - Google Patents

Nouveau sel de composé agoniste du récepteur glp-1, son procédé de préparation et composition pharmaceutique le comprenant Download PDF

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WO2023182869A1
WO2023182869A1 PCT/KR2023/003988 KR2023003988W WO2023182869A1 WO 2023182869 A1 WO2023182869 A1 WO 2023182869A1 KR 2023003988 W KR2023003988 W KR 2023003988W WO 2023182869 A1 WO2023182869 A1 WO 2023182869A1
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Prior art keywords
disease
diabetes
tromethamine salt
syndrome
salt
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Inventor
Hong Chul Yoon
Kyung Mi An
Joon Tae Park
Jung Woo Lee
Jung-Eun Park
Jae Eui SHIN
Min Whan CHANG
Mi Young Lee
Han Na Seo
Won Je Seong
Hyeong Jun Lee
In-gyu JE
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Ildong Pharmaceutical Co Ltd
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Ildong Pharmaceutical Co Ltd
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Priority to JP2024556591A priority Critical patent/JP2025510207A/ja
Priority to AU2023237572A priority patent/AU2023237572A1/en
Priority to EP23775364.5A priority patent/EP4499633A1/fr
Priority to CA3246495A priority patent/CA3246495A1/fr
Priority to US18/850,107 priority patent/US20250214968A1/en
Priority to CN202380030319.6A priority patent/CN119212991A/zh
Publication of WO2023182869A1 publication Critical patent/WO2023182869A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present disclosure relates to a novel salt of a glucagon-like peptide-1 receptor (GLP-1R) agonist compound exhibiting improved physical properties and excellent bioavailability in terms of stability, solubility, and the like, a preparation method thereof, and a pharmaceutical composition comprising the same.
  • GLP-1R glucagon-like peptide-1 receptor
  • GLP-1 glucagon-like peptide-1
  • GLP-1R glucagons-like peptide-1 receptor
  • GLP-1 analogs having resistance to the DPP-4 enzyme that destroys GLP-1 in the blood have been developed and are being used as treatments for type 2 diabetes. Since these GLP-1 analogues have a considerably longer half-life compared to GLP-1, they have the advantage of maintaining the hypoglycemic effect for a long time, but there is a problem of low medication convenience in that these GLP-1 analogues are not able to be administered orally and should be used in the form of injections. Therefore, in recent years, some studies have been conducted to discover a small-molecule GLP-1R agonist capable of being administered orally and develop the agonist as a therapeutic agent for diabetes.
  • An object of the present disclosure is to provide a novel salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid.
  • the present disclosure provides a novel salt having excellent physicochemical and/or pharmaceutical properties such as hygroscopicity, thermal stability, solubility, and the like, to have excellent formulation processability and storage stability, and excellent bioavailability, a preparation method thereof, and a pharmaceutical composition comprising the same.
  • the present disclosure provides a novel salt of (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid, a preparation method thereof, and a pharmaceutical composition comprising the same, as an active ingredient.
  • the present disclosure provides a tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid.
  • the tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid may be represented by the following Chemical Formula I:
  • novel salt according to the present disclosure exhibits excellent physicochemical and pharmacokinetic properties in various aspects such as thermal stability, in vivo solubility, bioavailability, and the like.
  • thermogravimetric analysis (TGA) pattern showing a weight loss of less than 1.0 wt%, 0.9 wt%, 0.8 wt%, 0.7 wt%, 0.6 wt%, 0.5 wt%, 0.4 wt%, 0.3 wt%, or 0.2 wt% at 170°C or less.
  • TGA thermogravimetric analysis
  • the tromethamine salt (specifically, crystalline form thereof) of the present disclosure is characterized by having an endothermic transition peak value at 174 to 204°C when a heating rate is 10°C/min in a differential scanning calorimetry (DSC) graph, and preferably, is characterized by having an endothermic transition peak value at 179 to 199°C, more preferably, at 184 to 194°C, and more preferably at 189 ⁇ 2°C.
  • DSC differential scanning calorimetry
  • the tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid of the present disclosure may show the differential scanning calorimetry of FIG. 2.
  • novel tromethamine salt of the present disclosure is preferably in a crystalline form.
  • the crystalline form of the tromethamine salt of the present disclosure may comprise, in an X-ray powder diffraction (XRPD) graph, at least three diffraction peaks at 2-theta (2 ⁇ ) angle values selected from the group consisting of 4.03 ⁇ 0.2, 8.09 ⁇ 0.2, 10.04 ⁇ 0.2, 15.07 ⁇ 0.2, 15.71 ⁇ 0.2, 17.90 ⁇ 0.2, 19.60 ⁇ 0.2, 22.07 ⁇ 0.2, 24.92 ⁇ 0.2, and 25.39 ⁇ 0.2.
  • XRPD X-ray powder diffraction
  • the crystalline form of the tromethamine salt of the present disclosure may comprise, in an X-ray powder diffraction (XRPD) graph, diffraction peaks at 2-theta (2 ⁇ ) angles of 4.03 ⁇ 0.2, 8.09 ⁇ 0.2, 10.04 ⁇ 0.2, 15.07 ⁇ 0.2, 15.71 ⁇ 0.2, 17.90 ⁇ 0.2, 19.60 ⁇ 0.2, 22.07 ⁇ 0.2, 24.92 ⁇ 0.2, and 25.39 ⁇ 0.2.
  • XRPD X-ray powder diffraction
  • the crystalline form of the tromethamine salt of the present disclosure may further comprise, in the XRPD graph, any one or more diffraction peaks at 2-theta (2 ⁇ ) angle values selected from the group consisting of 12.17 ⁇ 0.2, 14.39 ⁇ 0.2, 17.02 ⁇ 0.2, 20.18 ⁇ 0.2, and 21.81 ⁇ 0.2.
  • the tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid, having the aforementioned features, can be named crystalline form 1.
  • the crystalline form of the tromethamine salt of the present disclosure may further comprise, in the XRPD graph, any one or more diffraction peaks at 2-theta (2 ⁇ ) angle values selected from the group consisting of 19.80 ⁇ 0.2 and 24.53 ⁇ 0.2.
  • the crystalline form of the tromethamine salt of the present disclosure may further comprise, in the XRPD graph, diffraction peaks at 2-theta (2 ⁇ ) angle values 19.80 ⁇ 0.2 and 24.53 ⁇ 0.2, the crystalline form may be crystalline form 1A.
  • the tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid of the present disclosure may exhibit the X-ray powder diffraction spectroscopy pattern of FIG. 1.
  • the tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid may have excellent thermal stability, and stability according to temperature and humidity, thereby being stably maintained without a change in amount over a long period of time.
  • the tromethamine salt has excellent thermal stability against high temperature, and the like, to exhibit excellent storage stability. Therefore, the raw material of the novel salt of the present disclosure is able to be obtained in high yield and high purity, and the increase in related substances is remarkably low even when stored for a long time, and thus high purity may be maintained for a long period of time.
  • novel salt of the present disclosure may exhibit excellent solubility values under various pH conditions, particularly bio-relevant media conditions, to thereby have high bioavailability, thus achieving excellent pharmacological effects, and may be usefully employed as a new active ingredient of a pharmaceutical composition capable of treating various indications.
  • the novel salt according to the present disclosure when preparing stimulated gastric fluid (SGF), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) and performing a test for measuring solubility and dissolution under conditions close to the in vivo environment, good solubility was shown.
  • the solubility in FaSSIF was very good in the tromethamine salt.
  • the novel salt according to the present disclosure had significantly excellent solubility in vivo and exhibited high bioavailability.
  • the novel salt according to the present disclosure since the novel salt according to the present disclosure has high in vivo solubility to exhibit high levels of exposure in the body, and maintains a high blood concentration, thereby having a remarkable effect of excellent bioavailability.
  • novel salt of the present disclosure exhibits high bioavailability when administered orally, it is possible to exhibit excellent therapeutic effects even when taken in a small amount, thereby significantly improving the patient's medication compliance.
  • novel salt of the present disclosure may have a rapid onset of action and a thermodynamically stable form, and may be very advantageous in processing and storage of pharmaceutical products to achieve easy formulation, and further, may maintain the same state even after the formulation is prepared so that the uniformity in view of the formulation amount may be stably maintained for a long period of time, and thus the novel salt may be easily applied to mass production.
  • the said tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid, crystalline form 1, can be changed to crystalline form 1A upon exposure to atmospheric moisture at a specific relative humidity condition, specifically at 20°C and 55% RH or higher.
  • crystalline form 1A may return to the crystal form 1 upon desorption by changing the relative humidity conditions at 20°C, less than 55% RH, preferably 20°C, 50% RH or less, more preferably 20°C, 45% RH or less.
  • the tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid, crystalline form 1, according to the present disclosure is a non-stoichiometric hydrate, and when exposed to moisture in a wide range of atmosphere up to 90%RH, only expansion and contraction of the lattice due to water molecules occur, and there is no collapse of the lattice structure or crystal phase transition during adsorption and desorption. Therefore, even if the crystalline form of the tromethamine according to the present disclosure adsorbs moisture when exposed to a wide range of humidity, it can be reverted to the original crystalline form, which is the crystalline form 1, when desorbed.
  • the present disclosure provides a preparation method of a tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid represented by the following Chemical Formula I:
  • the preparation method of the present disclosure may be divided into the following steps:
  • step (1) (2) heating and warm-stirring a reaction solution obtained in step (1);
  • step (3) cooling and stirring a reaction solution obtained in step (2);
  • step (3) filtering and drying a product of step (3).
  • the compound represented by the following Chemical Formula II is ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid, which may be a free base prepared according to Comparative Example 1 of the present disclosure.
  • the organic solvent used in the reaction in step (1) may be a single organic solvent or a mixture of organic solvents.
  • the organic solvent may be one or a combination of two or more selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetonitrile, n-propanol, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, tetrahydrofuran, and 2-methyl tetrahydrofuran.
  • the organic solvent may be one or a combination of two or more organic solvents selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and ethyl acetate.
  • a mixing ratio of the mixed solvent may be 1 : 1 to 1 : 20 by volume.
  • tromethamine represented by Chemical Formula III is called tris(hydroxymethyl)aminomethane, and is also referred to as Tris.
  • Tris means tromethamine.
  • Tromethamine in step (1) is preferably used in an amount of 0.6 to 1.5 equivalents, more preferably in an amount of 0.7 to 1.3 equivalents, and still more preferably in an amount of 0.9 to 1.1 equivalents, based on 1.0 equivalent of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid.
  • the reacting in step (1) may be performed at a temperature of 20 to 80°C, preferably 40 to 70°C, and more preferably 55 to 60°C.
  • Step (2) may be a step of precipitating a solid precipitate
  • step (3) may be a step of separating the solid precipitate produced in step (2), wherein the solid precipitate may be separated by processes commonly performed in the relevant field, such as a principle separation method, and the like.
  • reaction temperature and time may be adjusted according to the type and amount of the sample and solvent used in the reaction, but are not limited to the above range.
  • the present disclosure provides a pharmaceutical composition for preventing or treating metabolic diseases comprising a tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid represented by the following Chemical Formula I;
  • novel tromethamine salt according to the present disclosure may have excellent stability, thermal stability, and pH stability, and may exhibit excellent in vivo solubility under bio-relevant media conditions close to the in vivo environment, thereby showing excellent pharmacological effects.
  • metabolic disease used herein includes, for example, diabetes (T1D and/or T2DM, such as prediabetes), idiopathic T1D (type 1b), latent autoimmune diabetes in adults (LADA), early onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, liver insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney failure, tubular dysfunction, pro-inflammatory changes to proximal tubule), diabetic retinopathy, adipocyte dysfunction, visceral fat accumulation, sleep apnea, obesity (e.g., hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g.
  • T1D and/or T2DM such as prediabetes), idiopathic T1D (type 1b), latent autoimmune diabetes in adults (LADA
  • osteoarthritis and urinary incontinence eating disorders (e.g., binge eating syndrome, anorexia nervosa, and syndrome of obesity, such as Prader-Willi syndrome and Bardet-Biedl syndrome), weight gain due to use of other drugs (e.g.
  • dyslipidemia including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, and low HDL cholesterol
  • hyperinsulinemia including hyperinsulinemia, NAFLD (including related diseases such as steatosis, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma)
  • cardiovascular disease atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, loss of vision, cataracts, glomerulosclerosis, chronic renal failure, metabolic dysfunction, e.g.
  • the metabolic disease may be at least any one selected from the group consisting of diabetes mellitus, idiopathic type 1 diabetes, latent autoimmune diabetes in adults (LADA), early onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, liver insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephrosis, kidney disease, diabetic retinopathy, visceral fat accumulation, sleep apnea, obesity, eating disorders, dyslipidemia, hyperinsulinemia, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, atherosclerosis, peripheral vascular disease, hypertension, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidemia, metabolic acidosis, metabolic acid
  • non-alcoholic fatty liver disease may be, for example, at least any one selected from the group consisting of steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma.
  • NASH non-alcoholic steatohepatitis
  • fibrosis fibrosis
  • cirrhosis cirrhosis
  • hepatocellular carcinoma hepatocellular carcinoma.
  • Exemplary non-alcoholic fatty liver diseases described above include a category of metabolic diseases having a significant association with various medical diseases excluding the category of alcoholic liver diseases.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising: a tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid represented by the following Chemical Formula I, and a pharmaceutically acceptable carrier:
  • pharmaceutically acceptable carrier includes any and all of physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • composition according to the present disclosure may be in various forms.
  • the composition according to the present disclosure may be in a form of, for example, liquid, semi-solid and solid dosage, such as liquid solutions (e.g., injectable and injectable solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • liquid solutions e.g., injectable and injectable solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • the form depends on the intended route of administration and therapeutic purpose thereof.
  • a typical composition is in the form of injectable and infusible solutions.
  • One mode of administration is a parenteral mode (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular mode).
  • Oral administration of a solid formulation may be achieved, for example, based on hard or soft capsules, pills, cachets, lozenges or tablets, each containing a predetermined amount of one or more compounds according to the present disclosure.
  • oral administration may be achieved based on powder or granular form.
  • oral administration may be achieved in a liquid dosage form.
  • the liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents (e.g., water) commonly used in the art.
  • compositions according to the present disclosure may be prepared by any well-known pharmaceutical technique, such as effective formulation and administration procedures.
  • formulations may be prepared by conventional methods used for formulation in the art or a method disclosed in the document [see, Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA], and may be formulated into various formulations depending on each disease or component.
  • composition of the present disclosure may be administered orally or parenterally (for example, intravenous, subcutaneous, intraperitoneal or topical application) according to the desired method, and the dose varies depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease.
  • the daily dose of the novel salt of the present disclosure is about 0.01 to 500 mg/kg, preferably 0.1 to 100 mg/kg, and may be divided and administered once or several times a day.
  • the pharmaceutical composition of the present disclosure may further contain at least one active ingredient exhibiting the same or similar medicinal effect in addition to the novel salt.
  • the present disclosure provides a pharmaceutical composition for the prevention or treatment of metabolic diseases, comprising: a tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid represented by the following Chemical Formula I:
  • the present disclosure provides a method for treating metabolic diseases, comprising: administering to a subject in need thereof a therapeutically effective amount of the tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid as described above.
  • a subject in need thereof means mammals including a human, which includes mammals such as humans, monkeys, cattle, horses, dogs, cats, rabbits, rats, and mice.
  • the term "therapeutically effective amount” refers to an amount of the novel salt effective for the prevention or treatment of metabolic diseases, or a pharmaceutical composition comprising the same, and for example, may include, as an amount of the novel salt to be administered to the subject to be treated, any amount of the pharmaceutical composition comprising the above-described salt, to prevent occurrence or recurrence of metabolic diseases, to alleviate symptoms, to inhibit direct or indirect pathological consequences, to prevent metastasis, to reduce the rate of progression, or to alleviate or temporarily ameliorate the condition or to improve the prognosis.
  • the therapeutically effective amount may be interpreted to encompass all doses in which symptoms of metabolic diseases are improved or cured by the pharmaceutical composition.
  • the method for preventing or treating metabolic diseases of the present disclosure includes not only treating the diseases themselves before the onset of signs, but also inhibiting or avoiding signs thereof by administering the above-described salt or the pharmaceutical composition comprising the same.
  • a prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered.
  • the dose and frequency of dose will vary depending on the age, weight and response of individual patients.
  • a suitable dosage regimen may be readily selected by one of ordinary skill in the art considering these factors naturally.
  • the method for treating metabolic diseases using the pharmaceutical composition of the present disclosure may further include administering a therapeutically effective amount of an additional active agent useful for treating the diseases together with the above-described salt, wherein the additional active agent may exhibit synergistic or auxiliary effects with the above-described salt which is an active ingredient according to the present disclosure.
  • the present disclosure also provides use of a tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid for the manufacture of a medicament for treatment of metabolic diseases.
  • the above-described salts for the manufacture of a medicament may be mixed with acceptable adjuvants, diluents, carriers, and the like, and may be prepared as a combined preparation with other active agents to have a synergistic action of the active ingredients.
  • novel salt according to the present disclosure may have excellent stability to increase the stability of the formulation, and may have improved solubility (particularly, in vivo solubility) and bioavailability to be usefully employed as an active ingredient of a pharmaceutical composition.
  • FIG. 1 is an X-ray powder diffraction analysis (XRPD) graph of a tromethamine salt compound represented by Chemical Formula I prepared in Example 3 of the present disclosure(crystalline form 1).
  • XRPD X-ray powder diffraction analysis
  • FIG. 2 is a thermogravimetric analysis (TGA) pattern analysis graph and a differential scanning calorimetry (DSC) pattern graph of the tromethamine salt compound represented by Chemical Formula I prepared in Example 3 of the present disclosure(crystalline form 1).
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • FIG. 3 is a thermogravimetric analysis (TGA) pattern analysis graph of a ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid free base prepared in Comparative Example 1.
  • TGA thermogravimetric analysis
  • FIG. 4 is a differential scanning calorimetry (DSC) pattern analysis graph of the ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid free base prepared in Comparative Example 1.
  • DSC differential scanning calorimetry
  • FIG. 5 is an X-ray powder diffraction analysis (XRPD) graph of an L-Arginine salt compound of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid prepared in Comparative Example 2.
  • XRPD X-ray powder diffraction analysis
  • FIG. 6 is a thermogravimetric analysis (TGA) pattern analysis graph of the L-Arginine salt compound of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid prepared in Comparative Example 2.
  • TGA thermogravimetric analysis
  • FIG. 7 is a differential scanning calorimetry (DSC) pattern analysis graph of the L-Arginine salt compound of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid prepared in Comparative Example 2.
  • DSC differential scanning calorimetry
  • FIG. 8 is an X-ray powder diffraction analysis (XRPD) graph of a meglumine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid prepared in Comparative Example 3.
  • XRPD X-ray powder diffraction analysis
  • FIG. 9 is a thermogravimetric analysis (TGA) pattern analysis graph of the meglumine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid prepared in Comparative Example 3.
  • TGA thermogravimetric analysis
  • FIG. 10 is a differential scanning calorimetry (DSC) pattern analysis graph of the meglumine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid prepared in Comparative Example 3.
  • DSC differential scanning calorimetry
  • FIG. 11 is an XRPD graph of a potassium salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid prepared in Comparative Example 4.
  • FIG. 12 is a TGA pattern analysis graph of the potassium salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid prepared in Comparative Example 4.
  • FIG. 13 is a DSC pattern analysis graph of the potassium salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid prepared in Comparative Example 4.
  • FIG. 14 is a graph showing results of dynamic vapor sorption (DVS) measurement of the tromethamine salt compound represented by Chemical Formula I prepared in Example 3 of the present disclosure(crystalline form 1).
  • DVD dynamic vapor sorption
  • FIG. 15 is a graph showing results of DVS measurement of the L-Arginine salt compound of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid prepared in Comparative Example 2.
  • FIG. 16 is a graph showing results of DVS measurement of the meglumine salt compound of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid prepared in Comparative Example 3.
  • FIG. 17 is a graph showing results of DVS measurement of the potassium salt compound of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid prepared in Comparative Example 4.
  • FIG. 18 is X-ray powder diffraction analysis (XRPD) graph of a tromethamine salt compound represented by Chemical Formula I prepared in Example 3 of the present disclosure(crystalline form 1), and crystalline form 1A analyzed under the conditions of 55%RH or higher at 20°C.
  • XRPD X-ray powder diffraction analysis
  • the X-ray powder diffraction (XRPD) pattern was measured using DYY884-AERIS-300 manufactured by PANalytical company, and analyzed with a step size of about 0.02° over the range of about 2° to 45° in the 2 ⁇ angle.
  • the conditions of use were set as shown in Table 1 below.
  • the ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid free base may be prepared in the same way as disclosed in Korean Patent Laid-Open Publication No. 10-2021-0059653, and the specific method thereof is as follows.
  • Step (1) Synthesis of methyl ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylate
  • the solution was diluted with ethyl acetate, and the organic layer was washed with a saturated NaHCO 3 aqueous solution, a saturated NH 4 Cl aqueous solution, and brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure to obtain a filtrate. The filtrate was concentrated under reduced pressure.
  • Step (2) Synthesis of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid
  • step (1) The compound (387 mg) obtained in step (1) was put into a round bottom flask, dissolved in acetonitrile (10 mL), and stirred. A 1.0 M TBD aqueous solution (1.4 mL) was added dropwise while stirring. Purified water (0.6 mL) was added to the mixture and stirred at 60°C for one day. After confirming the completion of the reaction by TLC, the mixture was neutralized to pH 7 with 1N HCl aqueous solution, extracted with a 10% DCM/MeOH solution, dried over anhydrous magnesium sulfate, and filtered under reduced pressure to obtain a filtrate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH) to obtain the final compound as a pale green solid (225 mg, yield 60%).
  • DCM/MeOH silica gel column chromatography
  • Thermogravimetric (TGA) analysis was performed on the tromethamine salt prepared in Example 3, the free base prepared in Comparative Example 1, the L-arginine salt prepared in Comparative Example 2, the meglumine salt prepared in Comparative Example 3, and the potassium salt prepared in Comparative Example 4.
  • Thermogravimetric analysis was performed from 20°C to 350°C at a heating rate of 10°C/min under nitrogen conditions using TGA Q50 manufactured by TA Instruments, Inc. The weight loss at about 170°C or less for each salt was measured, and results thereof are shown in FIG. 2 (tromethamine salt), FIG. 3 (free base), FIG. 6 (L-arginine salt), FIG. 9 (meglumine salt), and 12 (potassium salt), and summarized in Table 4 below.
  • DSC Differential scanning calorimetry
  • Hygroscopicity was measured for the tromethamine salt prepared in Example 3, the L-arginine salt prepared in Comparative Example 2, the meglumine salt prepared in Comparative Example 3, and the potassium salt prepared in Comparative Example 4. Results thereof are shown in FIGS. 14 to 17, respectively, and the results of the weight percent gain according to moisture sorption are shown in Table 6 below.
  • the tromethamine salt showed a weight change of about 1.44% when measuring the hygroscopicity through DVS at 25°C and 90% humidity, and exhibited significantly lower hygroscopicity compared to L-arginine salt, meglumine salt and potassium salt. Therefore, it was confirmed that the novel tromethamine salt of the present disclosure had excellent storage stability.
  • the tromethamine salt prepared in Example 3 and the free base prepared in Comparative Example 1 were stored for 24 hours at a temperature of 25°C and a relative humidity of 80%, and then the mass change of the sample due to moisture sorption was measured.
  • the tromethamine salt of the present disclosure had a coefficient of moisture absorption of 0.22%, and exhibited remarkably excellent non-hygroscopicity than the ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid free base.
  • the tromethamine salt of the present disclosure had remarkably excellent storage stability compared to the free base and was suitable for formulation.
  • Solubility in water and bio-relevant media i.e., stimulated gastric fluid (SGF), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) of the free base and the tromethamine salt of ( S )-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d ]imidazol-6-carboxylic acid was confirmed.
  • SGF stimulated gastric fluid
  • FaSSIF fasted state simulated intestinal fluid
  • FeSSIF fed state simulated intestinal fluid
  • Buffers for the bio-relevant media were prepared as follows.
  • SGF Stimulated Gastric Fluid
  • FaSSIF Fested State Simulated Intestinal Fluid
  • FeSSIF Fed State Simulated Intestinal Fluid
  • the tromethamine salt showed excellent solubility in all of SGF, FaSSIF, and FeSSIF, which regulate the pH similar to the in-vivo stomach, small intestine before meals, and small intestine after meals, but in particular exhibited very good solubility under fasted state simulated intestinal fluid (FaSSIF) conditions that mimic the small intestine where most drug absorption occurs.
  • FaSSIF fasted state simulated intestinal fluid
  • the stress conditions are as follows:
  • the tromethamine salt according to the present disclosure had a purity change rate of less than 1% under harsh conditions, showing remarkably excellent stability compared to that of the free base.
  • the tromethamine salt according to the present disclosure was a very stable material under harsh conditions that did not show any change in the XRPD pattern and had no change in appearance.
  • the crystalline form 1A has the 2 ⁇ diffraction pattern(2 ⁇ 0.2 °) shown in Table 3 above, and further comprises diffraction peaks at 2-theta (2 ⁇ ) angles of at 19.8019 ⁇ 0.2 and 24.5314 ⁇ 0.2.
  • the tromethamine salt of the present disclosure maintained the form of crystalline Form 1 under conditions 15%RH or more and less than 55%RH at 20°C.

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Abstract

La présente divulgation concerne un composé agoniste du récepteur GLP-1, et un nouveau sel de celui-ci ayant une excellente solubilité in vivo, une excellente stabilité et une excellente biodisponibilité, son procédé de préparation, et une composition pharmaceutique le comprenant.
PCT/KR2023/003988 2022-03-25 2023-03-24 Nouveau sel de composé agoniste du récepteur glp-1, son procédé de préparation et composition pharmaceutique le comprenant Ceased WO2023182869A1 (fr)

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JP2024556591A JP2025510207A (ja) 2022-03-25 2023-03-24 Ｇｌｐ－１ｒ受容体アゴニスト化合物の新規な塩、その製造方法およびこれを含む薬学組成物
AU2023237572A AU2023237572A1 (en) 2022-03-25 2023-03-24 Novel salt of glp-1 receptor agonist compound, preparation method thereof and pharmaceutical composition comprising thereof
EP23775364.5A EP4499633A1 (fr) 2022-03-25 2023-03-24 Nouveau sel de composé agoniste du récepteur glp-1, son procédé de préparation et composition pharmaceutique le comprenant
CA3246495A CA3246495A1 (fr) 2022-03-25 2023-03-24 Nouveau sel de composé agoniste du récepteur glp-1, son procédé de préparation et composition pharmaceutique le comprenant
US18/850,107 US20250214968A1 (en) 2022-03-25 2023-03-24 Novel Salt of GLP-1 Receptor Agonist Compound, Preparation Method Thereof and Pharmaceutical Composition Comprising Thereof
CN202380030319.6A CN119212991A (zh) 2022-03-25 2023-03-24 Glp-1受体激动剂化合物之新颖盐类、其制备方法以及包含其的药物组合物

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12234236B1 (en) 2023-09-14 2025-02-25 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
US12291530B1 (en) 2023-11-24 2025-05-06 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
WO2025128564A1 (fr) * 2023-12-11 2025-06-19 Carmot Therapeutics, Inc. Formes salines d'un modulateur du récepteur glp-1
WO2025158275A1 (fr) 2024-01-24 2025-07-31 Pfizer Inc. Polythérapie utilisant des composés antagonistes du récepteur du polypeptide insulinotrope glucose-dépendant et des composés agonistes du récepteur glp-1
WO2025189141A1 (fr) 2024-03-08 2025-09-12 Annapurna Bio, Inc. Méthodes de traitement de l'obésité et d'augmentation de la perte de poids

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KR20200131382A (ko) * 2019-05-13 2020-11-24 대원제약주식회사 펠루비프로펜의 신규 염, 이의 제조방법 및 이를 포함하는 약학적 조성물
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KR20190123607A (ko) * 2018-04-24 2019-11-01 (주)국전약품 피마살탄 트로메타민염 및 이를 포함하는 약제학적 조성물
KR20200131382A (ko) * 2019-05-13 2020-11-24 대원제약주식회사 펠루비프로펜의 신규 염, 이의 제조방법 및 이를 포함하는 약학적 조성물
KR20210059584A (ko) * 2019-11-15 2021-05-25 일동제약(주) Glp-1 수용체 작용제 및 이의 용도
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12234236B1 (en) 2023-09-14 2025-02-25 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
US12291530B1 (en) 2023-11-24 2025-05-06 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
WO2025128564A1 (fr) * 2023-12-11 2025-06-19 Carmot Therapeutics, Inc. Formes salines d'un modulateur du récepteur glp-1
WO2025158275A1 (fr) 2024-01-24 2025-07-31 Pfizer Inc. Polythérapie utilisant des composés antagonistes du récepteur du polypeptide insulinotrope glucose-dépendant et des composés agonistes du récepteur glp-1
WO2025189141A1 (fr) 2024-03-08 2025-09-12 Annapurna Bio, Inc. Méthodes de traitement de l'obésité et d'augmentation de la perte de poids

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